04872nas a2201453 4500008004100000022001400041245010900055210006900164260001600233300000900249490000600258520072200264653002100986653003401007653001101041653005101052653002101103653003601124100001801160700002001178700002501198700002301223700001601246700002101262700002301283700001701306700002501323700002401348700002201372700002201394700001901416700001701435700002001452700001201472700002101484700002101505700002801526700002301554700002501577700002001602700002401622700001401646700002601660700002001686700001901706700002401725700001701749700001801766700001901784700002201803700001801825700002201843700001901865700002601884700002101910700002501931700002401956700001801980700002501998700002202023700002102045700001702066700002402083700001602107700001602123700001902139700002202158700001602180700001902196700001902215700001802234700002302252700001902275700002102294700001802315700002102333700002002354700003002374700002702404700001602431700002202447700001802469700001602487700001702503700002302520700001602543700002202559700002102581700002602602700002002628700002502648700002802673700002402701700002302725700002202748700001902770700002302789700002302812700002202835700002002857700002302877700002802900700001902928700002602947700002002973700002102993700002003014700002403034700001703058700002103075700002803096700002203124700002203146700002003168700002303188700002403211700002203235700001903257700002203276700001903298700002303317710004203340856003603382 2014 eng d a2041-172300aPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.0 aPharmacogenetic metaanalysis of genomewide association studies o c2014 Oct 28 a50680 v53 a
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
10aCholesterol, LDL10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide1 aPostmus, Iris1 aTrompet, Stella1 aDeshmukh, Harshal, A1 aBarnes, Michael, R1 aLi, Xiaohui1 aWarren, Helen, R1 aChasman, Daniel, I1 aZhou, Kaixin1 aArsenault, Benoit, J1 aDonnelly, Louise, A1 aWiggins, Kerri, L1 aAvery, Christy, L1 aGriffin, Paula1 aFeng, QiPing1 aTaylor, Kent, D1 aLi, Guo1 aEvans, Daniel, S1 aSmith, Albert, V1 ade Keyser, Catherine, E1 aJohnson, Andrew, D1 ade Craen, Anton, J M1 aStott, David, J1 aBuckley, Brendan, M1 aFord, Ian1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aSattar, Naveed1 aMunroe, Patricia, B1 aSever, Peter1 aPoulter, Neil1 aStanton, Alice1 aShields, Denis, C1 aO'Brien, Eoin1 aShaw-Hawkins, Sue1 aChen, Y-D, Ida1 aNickerson, Deborah, A1 aSmith, Joshua, D1 aDubé, Marie, Pierre1 aBoekholdt, Matthijs1 aHovingh, Kees1 aKastelein, John, J P1 aMcKeigue, Paul, M1 aBetteridge, John1 aNeil, Andrew1 aDurrington, Paul, N1 aDoney, Alex1 aCarr, Fiona1 aMorris, Andrew1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aBis, Joshua, C1 aRice, Kenneth1 aSmith, Nicholas, L1 aLumley, Thomas1 aWhitsel, Eric, A1 aStürmer, Til1 aBoerwinkle, Eric1 aNgwa, Julius, S1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWei, Wei-Qi1 aWilke, Russell, A1 aLiu, Ching-Ti1 aSun, Fangui1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aPost, Wendy1 aSotoodehnia, Nona1 aArnold, Alice, M1 aStafford, Jeanette, M1 aDing, Jingzhong1 aHerrington, David, M1 aKritchevsky, Stephen, B1 aEiriksdottir, Gudny1 aLauner, Leonore, J1 aHarris, Tamara, B1 aChu, Audrey, Y1 aGiulianini, Franco1 aMacFadyen, Jean, G1 aBarratt, Bryan, J1 aNyberg, Fredrik1 aStricker, Bruno, H1 aUitterlinden, André, G1 aHofman, Albert1 aRivadeneira, Fernando1 aEmilsson, Valur1 aFranco, Oscar, H1 aRidker, Paul, M1 aGudnason, Vilmundur1 aLiu, Yongmei1 aDenny, Joshua, C1 aBallantyne, Christie, M1 aRotter, Jerome, I1 aCupples, Adrienne1 aPsaty, Bruce, M1 aPalmer, Colin, N A1 aTardif, Jean-Claude1 aColhoun, Helen, M1 aHitman, Graham1 aKrauss, Ronald, M1 aJukema, Wouter1 aCaulfield, Mark, J1 aWelcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/659104724nas a2201189 4500008004100000022001400041245009300055210006900148260001300217300001200230490000700242520135800249100001801607700002101625700002001646700002501666700002201691700001901713700002301732700002801755700002501783700002101808700001701829700001601846700002201862700002101884700001601905700002001921700002101941700002301962700002201985700002102007700002402028700002102052700002402073700001902097700002502116700002402141700002102165700002502186700002402211700002402235700001402259700001702273700002202290700002302312700001902335700001802354700002502372700002302397700001802420700001702438700001902455700002202474700002402496700001702520700002602537700002002563700001802583700003002601700001602631700001802647700002702665700001802692700002102710700002602731700001902757700001702776700002202793700002202815700002002837700002302857700002102880700002202901700001902923700002002942700002302962700001802985700002803003700001603031700002603047700002103073700002203094700002203116700002803138700002203166700002503188700002103213700002403234700001903258700002303277700002003300700002003320700002603340700002203366700002403388700002303412700001903435700002203454700002203476856003603498 2016 eng d a1468-624400aMeta-analysis of genome-wide association studies of HDL cholesterol response to statins.0 aMetaanalysis of genomewide association studies of HDL cholestero c2016 Dec a835-8450 v533 aBACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
1 aPostmus, Iris1 aWarren, Helen, R1 aTrompet, Stella1 aArsenault, Benoit, J1 aAvery, Christy, L1 aBis, Joshua, C1 aChasman, Daniel, I1 ade Keyser, Catherine, E1 aDeshmukh, Harshal, A1 aEvans, Daniel, S1 aFeng, QiPing1 aLi, Xiaohui1 aSmit, Roelof, A J1 aSmith, Albert, V1 aSun, Fangui1 aTaylor, Kent, D1 aArnold, Alice, M1 aBarnes, Michael, R1 aBarratt, Bryan, J1 aBetteridge, John1 aBoekholdt, Matthijs1 aBoerwinkle, Eric1 aBuckley, Brendan, M1 aChen, Y-D, Ida1 ade Craen, Anton, J M1 aCummings, Steven, R1 aDenny, Joshua, C1 aDubé, Marie, Pierre1 aDurrington, Paul, N1 aEiriksdottir, Gudny1 aFord, Ian1 aGuo, Xiuqing1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHofman, Albert1 aHovingh, Kees1 aKastelein, John, J P1 aLauner, Leonore, J1 aLiu, Ching-Ti1 aLiu, Yongmei1 aLumley, Thomas1 aMcKeigue, Paul, M1 aMunroe, Patricia, B1 aNeil, Andrew1 aNickerson, Deborah, A1 aNyberg, Fredrik1 aO'Brien, Eoin1 aO'Donnell, Christopher, J1 aPost, Wendy1 aPoulter, Neil1 aVasan, Ramachandran, S1 aRice, Kenneth1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSattar, Naveed1 aSever, Peter1 aShaw-Hawkins, Sue1 aShields, Denis, C1 aSlagboom, Eline1 aSmith, Nicholas, L1 aSmith, Joshua, D1 aSotoodehnia, Nona1 aStanton, Alice1 aStott, David, J1 aStricker, Bruno, H1 aStürmer, Til1 aUitterlinden, André, G1 aWei, Wei-Qi1 aWestendorp, Rudi, G J1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aWilke, Russell, A1 aBallantyne, Christie, M1 aColhoun, Helen, M1 aCupples, Adrienne, L1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aHitman, Graham1 aPalmer, Colin, N A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aStafford, Jeanette, M1 aStein, Charles, M1 aTardif, Jean-Claude1 aCaulfield, Mark, J1 aJukema, Wouter1 aRotter, Jerome, I1 aKrauss, Ronald, M uhttps://chs-nhlbi.org/node/735806088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736309668nas a2203061 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2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757304580nas a2200937 4500008004100000022001400041245022100055210006900276260001300345300001200358490000700370520179400377100002102171700002402192700002202216700002202238700002702260700002202287700002002309700002102329700001602350700002102366700001602387700001202403700002102415700001902436700002302455700001902478700002302497700002102520700002402541700002502565700001502590700002102605700002902626700002202655700002302677700002202700700001902722700002002741700001702761700002202778700001202800700002002812700002102832700001802853700002302871700002302894700002902917700001802946700002502964700002102989700001903010700002503029700002403054700001903078700001703097700002303114700002003137700002403157700002203181700002003203700001803223700002003241700002503261700002803286700002403314700002103338700002403359700001903383700002103402700001703423700002903440700002403469700002203493700002703515700002003542700002303562700002103585856003603606 2017 eng d a1468-624400aA genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.0 agenomewide interaction analysis of tricyclictetracyclic antidepr c2017 May a313-3230 v543 aBACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.
METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.
CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
1 aNoordam, Raymond1 aSitlani, Colleen, M1 aAvery, Christy, L1 aStewart, James, D1 aGogarten, Stephanie, M1 aWiggins, Kerri, L1 aTrompet, Stella1 aWarren, Helen, R1 aSun, Fangui1 aEvans, Daniel, S1 aLi, Xiaohui1 aLi, Jin1 aSmith, Albert, V1 aBis, Joshua, C1 aBrody, Jennifer, A1 aBusch, Evan, L1 aCaulfield, Mark, J1 aChen, Yii-der, I1 aCummings, Steven, R1 aCupples, Adrienne, L1 aDuan, Qing1 aFranco, Oscar, H1 aMéndez-Giráldez, Rául1 aHarris, Tamara, B1 aHeckbert, Susan, R1 avan Heemst, Diana1 aHofman, Albert1 aFloyd, James, S1 aKors, Jan, A1 aLauner, Lenore, J1 aLi, Yun1 aLi-Gao, Ruifang1 aLange, Leslie, A1 aLin, Henry, J1 ade Mutsert, Renée1 aNapier, Melanie, D1 aNewton-Cheh, Christopher1 aPoulter, Neil1 aReiner, Alexander, P1 aRice, Kenneth, M1 aRoach, Jeffrey1 aRodriguez, Carlos, J1 aRosendaal, Frits, R1 aSattar, Naveed1 aSever, Peter1 aSeyerle, Amanda, A1 aSlagboom, Eline1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStott, David, J1 aStürmer, Til1 aTaylor, Kent, D1 aThornton, Timothy, A1 aUitterlinden, André, G1 aWilhelmsen, Kirk, C1 aWilson, James, G1 aGudnason, Vilmundur1 aJukema, Wouter1 aLaurie, Cathy, C1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aStricker, Bruno, H1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/735307019nas a2201849 4500008004100000022001400041245009300055210006900148260001300217490000700230520169900237100001901936700001901955700002101974700002301995700001602018700002502034700002202059700001802081700001902099700001702118700002602135700001602161700003002177700002302207700002102230700002502251700002002276700002102296700002302317700001602340700002302356700002002379700001702399700002102416700002302437700002202460700001402482700002502496700002902521700002402550700002102574700001802595700001702613700002502630700001802655700001802673700002002691700002202711700002502733700001302758700002002771700002402791700002502815700001902840700001902859700002102878700002702899700001902926700001402945700002402959700002302983700002203006700002503028700002603053700002303079700002203102700002103124700002003145700001803165700002603183700001703209700001803226700002303244700002403267700001203291700002103303700002103324700002203345700002103367700002703388700002303415700001803438700002203456700002003478700002403498700001803522700001903540700002103559700001603580700002003596700002303616700002003639700002203659700001603681700002103697700001903718700002203737700001703759700002003776700002303796700002703819700002403846700001903870700002203889700001903911700002403930700001503954700002003969700001903989700002204008700001904030700002104049700002204070700002304092700001904115700001904134700002104153700002504174700002004199700002004219700002204239700001604261700002004277700002204297700002004319700001604339700002604355700001904381700001504400700002404415700002304439700002604462700002404488700002504512700002104537700002304558700002104581700002404602700002104626700002504647700001704672700002704689700002004716700002004736700002304756700002304779700001804802700002504820700001704845700002904862700002404891700002404915710004304939710015104982856003605133 2017 eng d a1942-326800aNew Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.0 aNew Blood PressureAssociated Loci Identified in MetaAnalyses of c2017 Oct0 v103 aBACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
1 aKraja, Aldi, T1 aCook, James, P1 aWarren, Helen, R1 aSurendran, Praveen1 aLiu, Chunyu1 aEvangelou, Evangelos1 aManning, Alisa, K1 aGrarup, Niels1 aDrenos, Fotios1 aSim, Xueling1 aSmith, Albert, Vernon1 aAmin, Najaf1 aBlakemore, Alexandra, I F1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aFarmaki, Aliki-Eleni1 aFava, Cristiano1 aFerreira, Teresa1 aHerzig, Karl-Heinz1 aGiri, Ayush1 aGiulianini, Franco1 aGrove, Megan, L1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHave, Christian, T1 aHavulinna, Aki, S1 aZhang, He1 aJørgensen, Marit, E1 aKäräjämäki, AnneMari1 aKooperberg, Charles1 aLinneberg, Allan1 aLittle, Louis1 aLiu, Yongmei1 aBonnycastle, Lori, L1 aLu, Yingchang1 aMägi, Reedik1 aMahajan, Anubha1 aMalerba, Giovanni1 aMarioni, Riccardo, E1 aMei, Hao1 aMenni, Cristina1 aMorrison, Alanna, C1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRayner, Nigel, William1 aRiaz, Muhammad1 aRice, Ken1 aRichard, Melissa, A1 aSmith, Jennifer, A1 aSoutham, Lorraine1 aStančáková, Alena1 aStirrups, Kathleen, E1 aTragante, Vinicius1 aTuomi, Tiinamaija1 aTzoulaki, Ioanna1 aVarga, Tibor, V1 aWeiss, Stefan1 aYiorkas, Andrianos, M1 aYoung, Robin1 aZhang, Weihua1 aBarnes, Michael, R1 aCabrera, Claudia, P1 aGao, He1 aBoehnke, Michael1 aBoerwinkle, Eric1 aChambers, John, C1 aConnell, John, M1 aChristensen, Cramer, K1 ade Boer, Rudolf, A1 aDeary, Ian, J1 aDedoussis, George1 aDeloukas, Panos1 aDominiczak, Anna, F1 aDörr, Marcus1 aJoehanes, Roby1 aEdwards, Todd, L1 aEsko, Tõnu1 aFornage, Myriam1 aFranceschini, Nora1 aFranks, Paul, W1 aGambaro, Giovanni1 aGroop, Leif1 aHallmans, Göran1 aHansen, Torben1 aHayward, Caroline1 aHeikki, Oksa1 aIngelsson, Erik1 aTuomilehto, Jaakko1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, S1 aLakka, Timo, A1 aLangenberg, Claudia1 aLind, Lars1 aLoos, Ruth, J F1 aLaakso, Markku1 aMcCarthy, Mark, I1 aMelander, Olle1 aMohlke, Karen, L1 aMorris, Andrew, P1 aPalmer, Colin, N A1 aPedersen, Oluf1 aPolasek, Ozren1 aPoulter, Neil, R1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSever, Peter, J1 aSkaaby, Tea1 aStafford, Jeanette, M1 aStarr, John, M1 aHarst, Pim1 avan der Meer, Peter1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aGudnason, Vilmundur1 aWareham, Nicholas, J1 aWilson, James, G1 aWiller, Cristen, J1 aWitte, Daniel, R1 aZeggini, Eleftheria1 aSaleheen, Danish1 aButterworth, Adam, S1 aDanesh, John1 aAsselbergs, Folkert, W1 aWain, Louise, V1 aEhret, Georg, B1 aChasman, Daniel, I1 aCaulfield, Mark, J1 aElliott, Paul1 aLindgren, Cecilia, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aHowson, Joanna, M M1 aUnderstanding Society Scientific Group1 aCHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† uhttps://chs-nhlbi.org/node/756909467nas a2203025 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2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749205196nas a2201345 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2018 eng d a2574-830000aCommon and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.0 aCommon and Rare Coding Genetic Variation Underlying the Electroc c2018 May ae0020370 v113 aBACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.
METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.
RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.
CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
1 aLin, Honghuang1 avan Setten, Jessica1 aSmith, Albert, V1 aBihlmeyer, Nathan, A1 aWarren, Helen, R1 aBrody, Jennifer, A1 aRadmanesh, Farid1 aHall, Leanne1 aGrarup, Niels1 aMüller-Nurasyid, Martina1 aBoutin, Thibaud1 aVerweij, Niek1 aLin, Henry, J1 aLi-Gao, Ruifang1 avan den Berg, Marten, E1 aMarten, Jonathan1 aWeiss, Stefan1 aPrins, Bram, P1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aMei, Hao1 aHarris, Tamara, B1 aLauner, Lenore, J1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aConnell, John, M1 aHuang, Paul, L1 aWeng, Lu-Chen1 aJameson, Heather, S1 aHucker, William1 aHanley, Alan1 aTucker, Nathan, R1 aChen, Yii-Der Ida1 aBis, Joshua, C1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aKors, Jan, A1 aXie, Zhijun1 aWen, Chengping1 aMagnani, Jared, W1 aNelson, Christopher, P1 aKanters, Jørgen, K1 aSinner, Moritz, F1 aStrauch, Konstantin1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aBork-Jensen, Jette1 aPedersen, Oluf1 aLinneberg, Allan1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aEijgelsheim, Mark1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aVölzke, Henry1 aFelix, Stephan, B1 aHomuth, Georg1 aVölker, Uwe1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aKähönen, Mika1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aArking, Dan, E1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aSamani, Nilesh, J1 aHansen, Torben1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aJukema, Wouter1 aStricker, Bruno, H1 aHayward, Caroline1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aWilson, James, G1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aIsaacs, Aaron uhttps://chs-nhlbi.org/node/780105658nas a2201489 4500008004100000022001400041245010600055210006900161260001500230300000700245490000700252520146500259100001901724700002101743700002301764700002701787700001901814700002501833700002501858700002301883700002501906700002901931700002201960700002301982700001702005700001702022700001802039700002202057700002002079700002102099700001802120700002002138700001902158700001802177700002802195700002102223700001302244700003002257700001902287700002502306700002102331700001902352700002302371700002002394700002402414700002102438700001802459700002102477700001802498700001902516700002002535700002102555700002302576700002402599700002202623700002402645700001702669700002202686700002202708700002202730700002302752700001902775700001702794700002002811700001702831700002202848700002202870700001202892700002102904700002702925700001902952700001702971700002002988700001903008700002003027700002303047700002103070700002203091700002203113700002403135700002003159700002403179700002803203700001903231700002003250700002403270700002103294700002403315700001703339700001903356700002603375700002103401700001603422700002703438700001803465700002303483700002103506700002803527700002403555700001903579700001903598700002403617700002403641700002203665700001803687700002203705700002903727700002403756700003203780700002103812700001603833700002203849700002403871700002003895700001603915700002303931700001803954700002203972700002003994700001504014700002104029700002404050700001904074700001904093700002004112856003604132 2018 eng d a1474-760X00aExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.0 aExomechip metaanalysis identifies novel loci associated with car c2018 07 17 a870 v193 aBACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.
RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.
CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
1 aPrins, Bram, P1 aMead, Timothy, J1 aBrody, Jennifer, A1 aSveinbjornsson, Gardar1 aNtalla, Ioanna1 aBihlmeyer, Nathan, A1 avan den Berg, Marten1 aBork-Jensen, Jette1 aCappellani, Stefania1 aVan Duijvenboden, Stefan1 aKlena, Nikolai, T1 aGabriel, George, C1 aLiu, Xiaoqin1 aGulec, Cagri1 aGrarup, Niels1 aHaessler, Jeffrey1 aHall, Leanne, M1 aIorio, Annamaria1 aIsaacs, Aaron1 aLi-Gao, Ruifang1 aLin, Honghuang1 aLiu, Ching-Ti1 aLyytikäinen, Leo-Pekka1 aMarten, Jonathan1 aMei, Hao1 aMüller-Nurasyid, Martina1 aOrini, Michele1 aPadmanabhan, Sandosh1 aRadmanesh, Farid1 aRamirez, Julia1 aRobino, Antonietta1 aSchwartz, Molly1 avan Setten, Jessica1 aSmith, Albert, V1 aVerweij, Niek1 aWarren, Helen, R1 aWeiss, Stefan1 aAlonso, Alvaro1 aArnar, David, O1 aBots, Michiel, L1 ade Boer, Rudolf, A1 aDominiczak, Anna, F1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aGuo, Xiuqing1 aFelix, Stephan, B1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHuang, Paul, L1 aJukema, J, W1 aKähönen, Mika1 aKors, Jan, A1 aLambiase, Pier, D1 aLauner, Lenore, J1 aLi, Man1 aLinneberg, Allan1 aNelson, Christopher, P1 aPedersen, Oluf1 aPerez, Marco1 aPeters, Annette1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRotter, Jerome, I1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Tim, D1 aStrauch, Konstantin1 aThorsteinsdottir, Unnur1 aTinker, Andrew1 aTrompet, Stella1 aUitterlinden, Andre1 aVaartjes, Ilonca1 avan der Meer, Peter1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWilson, James, G1 aXie, Zhijun1 aAsselbergs, Folkert, W1 aDörr, Marcus1 aDuijn, Cornelia, M1 aGasparini, Paolo1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHansen, Torben1 aKääb, Stefan1 aKanters, Jørgen, K1 aKooperberg, Charles1 aLehtimäki, Terho1 aLin, Henry, J1 aLubitz, Steven, A1 aMook-Kanamori, Dennis, O1 aConti, Francesco, J1 aNewton-Cheh, Christopher, H1 aRosand, Jonathan1 aRudan, Igor1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aSmith, Blair, H1 aHolm, Hilma1 aStricker, Bruno, H1 aUlivi, Sheila1 aSotoodehnia, Nona1 aApte, Suneel, S1 aHarst, Pim1 aStefansson, Kari1 aMunroe, Patricia, B1 aArking, Dan, E1 aLo, Cecilia, W1 aJamshidi, Yalda uhttps://chs-nhlbi.org/node/780905298nas a2201333 4500008004100000022001400041245011200055210006900167260001300236300001200249490000700261520154600268100002501814700002301839700002601862700002101888700001901909700001801928700001801946700002101964700002101985700002002006700001802026700001302044700003002057700002502087700001802112700001702130700001302147700002002160700002502180700001802205700001902223700002402242700002202266700002802288700001202316700001902328700002402347700001902371700001602390700002202406700002002428700002302448700002202471700002502493700002102518700001902539700001602558700002402574700001702598700002102615700002202636700002702658700002102685700002302706700001902729700001902748700002102767700002202788700002002810700002602830700002202856700002002878700001802898700001602916700002302932700002402955700001802979700002002997700002303017700002003040700001903060700001803079700002503097700002603122700002403148700001703172700001803189700001903207700002203226700002103248700002403269700002103293700001703314700002303331700002003354700001803374700002403392700002403416700002203440700002303462700003203485700002203517700002103539700002203560700002403582700002103606700001903627700001903646700001503665700002303680700002203703700002903725700002203754700001803776700002003794700002703814700002403841700002203865700001903887700002203906856003603928 2018 eng d a2574-830000aExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.0 aExomeChipWide Analysis of 95 626 Individuals Identifies 10 Novel c2018 Jan ae0017580 v113 aBACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.
METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.
CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aWarren, Helen, R1 aLin, Honghuang1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aMarten, Jonathan1 aRadmanesh, Farid1 aHall, Leanne, M1 aGrarup, Niels1 aMei, Hao1 aMüller-Nurasyid, Martina1 aHuffman, Jennifer, E1 aVerweij, Niek1 aGuo, Xiuqing1 aYao, Jie1 aLi-Gao, Ruifang1 avan den Berg, Marten1 aWeiss, Stefan1 aPrins, Bram, P1 avan Setten, Jessica1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aBis, Joshua, C1 aAustin, Tom1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aHarrris, Tamara, B1 aLauner, Lenore, J1 aPadmanabhan, Sandosh1 aDominiczak, Anna1 aHuang, Paul, L1 aXie, Zhijun1 aEllinor, Patrick, T1 aKors, Jan, A1 aCampbell, Archie1 aMurray, Alison, D1 aNelson, Christopher, P1 aTobin, Martin, D1 aBork-Jensen, Jette1 aHansen, Torben1 aPedersen, Oluf1 aLinneberg, Allan1 aSinner, Moritz, F1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPerz, Siegfried1 aKolcic, Ivana1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aLin, Henry, J1 aTaylor, Kent, D1 ade Mutsert, Renée1 aTrompet, Stella1 aJukema, Wouter1 aMaan, Arie, C1 aStricker, Bruno, H C1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aVölker, Uwe1 aHomuth, Georg1 aVölzke, Henry1 aFelix, Stephan, B1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aRaitakari, Olli, T1 aKähönen, Mika1 aMononen, Nina1 aGudnason, Vilmundur1 aMunroe, Patricia, B1 aLubitz, Steven, A1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher, H1 aHayward, Caroline1 aRosand, Jonathan1 aSamani, Nilesh, J1 aKanters, Jørgen, K1 aWilson, James, G1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aEijgelsheim, Mark1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/778410328nas a2203505 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2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, 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aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768611027nas a2203421 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2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779209584nas a2203049 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2018 eng d a1546-171800aRefining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.0 aRefining the accuracy of validated target identification through c2018 Apr a559-5710 v503 aWe aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
1 aMahajan, Anubha1 aWessel, Jennifer1 aWillems, Sara, M1 aZhao, Wei1 aRobertson, Neil, R1 aChu, Audrey, Y1 aGan, Wei1 aKitajima, Hidetoshi1 aTaliun, Daniel1 aRayner, William1 aGuo, Xiuqing1 aLu, Yingchang1 aLi, Man1 aJensen, Richard, A1 aHu, Yao1 aHuo, Shaofeng1 aLohman, Kurt, K1 aZhang, Weihua1 aCook, James, P1 aPrins, Bram, Peter1 aFlannick, Jason1 aGrarup, Niels1 aTrubetskoy, Vassily, Vladimirov1 aKravic, Jasmina1 aKim, Young, Jin1 aRybin, Denis, V1 aYaghootkar, Hanieh1 aMüller-Nurasyid, Martina1 aMeidtner, Karina1 aLi-Gao, Ruifang1 aVarga, Tibor, V1 aMarten, Jonathan1 aLi, Jin1 aSmith, Albert, Vernon1 aAn, Ping1 aLigthart, Symen1 aGustafsson, Stefan1 aMalerba, Giovanni1 aDemirkan, Ayse1 aTajes, Juan, Fernandez1 aSteinthorsdottir, Valgerdur1 aWuttke, Matthias1 aLecoeur, Cécile1 aPreuss, Michael1 aBielak, Lawrence, F1 aGraff, Marielisa1 aHighland, Heather, M1 aJustice, Anne, E1 aLiu, Dajiang, J1 aMarouli, Eirini1 aPeloso, Gina, Marie1 aWarren, Helen, R1 aAfaq, Saima1 aAfzal, Shoaib1 aAhlqvist, Emma1 aAlmgren, Peter1 aAmin, Najaf1 aBang, Lia, B1 aBertoni, Alain, G1 aBombieri, Cristina1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBurtt, Noel, P1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aCho, Yoon Shin1 aChristensen, Cramer1 aEastwood, Sophie, V1 aEckardt, Kai-Uwe1 aFischer, Krista1 aGambaro, Giovanni1 aGiedraitis, Vilmantas1 aGrove, Megan, L1 ade Haan, Hugoline, G1 aHackinger, Sophie1 aHai, Yang1 aHan, Sohee1 aTybjærg-Hansen, Anne1 aHivert, Marie-France1 aIsomaa, Bo1 aJäger, Susanne1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKäräjämäki, AnneMari1 aKim, Bong-Jo1 aKim, Sung, Soo1 aKoistinen, Heikki, A1 aKovacs, Peter1 aKriebel, Jennifer1 aKronenberg, Florian1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Jung-Jin1 aLehne, Benjamin1 aLi, Huaixing1 aLin, Keng-Hung1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jun1 aLoh, Marie1 aMägi, Reedik1 aMamakou, Vasiliki1 aMcKean-Cowdin, Roberta1 aNadkarni, Girish1 aNeville, Matt1 aNielsen, Sune, F1 aNtalla, Ioanna1 aPeyser, Patricia, A1 aRathmann, Wolfgang1 aRice, Kenneth1 aRich, Stephen, S1 aRode, Line1 aRolandsson, Olov1 aSchönherr, Sebastian1 aSelvin, Elizabeth1 aSmall, Kerrin, S1 aStančáková, Alena1 aSurendran, Praveen1 aTaylor, Kent, D1 aTeslovich, Tanya, M1 aThorand, Barbara1 aThorleifsson, Gudmar1 aTin, Adrienne1 aTönjes, Anke1 aVarbo, Anette1 aWitte, Daniel, R1 aWood, Andrew, R1 aYajnik, Pranav1 aYao, Jie1 aYengo, Loic1 aYoung, Robin1 aAmouyel, Philippe1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aChowdhury, Raj1 aCollins, Francis, S1 aDedoussis, George1 aDehghan, Abbas1 aDeloukas, Panos1 aFerrario, Marco, M1 aFerrieres, Jean1 aFlorez, Jose, C1 aFrossard, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHowson, Joanna, M M1 aIngelsson, Martin1 aKathiresan, Sekar1 aKee, Frank1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLindgren, Cecilia, M1 aMännistö, Satu1 aMeitinger, Thomas1 aMelander, Olle1 aMohlke, Karen, L1 aMoitry, Marie1 aMorris, Andrew, D1 aMurray, Alison, D1 ade Mutsert, Renée1 aOrho-Melander, Marju1 aOwen, Katharine, R1 aPerola, Markus1 aPeters, Annette1 aProvince, Michael, A1 aRasheed, Asif1 aRidker, Paul, M1 aRivadineira, Fernando1 aRosendaal, Frits, R1 aRosengren, Anders, H1 aSalomaa, Veikko1 aSheu, Wayne, H-H1 aSladek, Rob1 aSmith, Blair, H1 aStrauch, Konstantin1 aUitterlinden, André, G1 aVarma, Rohit1 aWiller, Cristen, J1 aBlüher, Matthias1 aButterworth, Adam, S1 aChambers, John, Campbell1 aChasman, Daniel, I1 aDanesh, John1 aDuijn, Cornelia1 aDupuis, Josée1 aFranco, Oscar, H1 aFranks, Paul, W1 aFroguel, Philippe1 aGrallert, Harald1 aGroop, Leif1 aHan, Bok-Ghee1 aHansen, Torben1 aHattersley, Andrew, T1 aHayward, Caroline1 aIngelsson, Erik1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, Singh1 aKöttgen, Anna1 aKuulasmaa, Kari1 aLaakso, Markku1 aLin, Xu1 aLind, Lars1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMarchini, Jonathan1 aMetspalu, Andres1 aMook-Kanamori, Dennis1 aNordestgaard, Børge, G1 aPalmer, Colin, N A1 aPankow, James, S1 aPedersen, Oluf1 aPsaty, Bruce, M1 aRauramaa, Rainer1 aSattar, Naveed1 aSchulze, Matthias, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aThorsteinsdottir, Unnur1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aWareham, Nicholas, J1 aWilson, James, G1 aZeggini, Eleftheria1 aScott, Robert, A1 aBarroso, Inês1 aFrayling, Timothy, M1 aGoodarzi, Mark, O1 aMeigs, James, B1 aBoehnke, Michael1 aSaleheen, Danish1 aMorris, Andrew, P1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aExomeBP Consortium1 aMAGIC Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/766815950nas a2205365 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
1 aClark, David, W1 aOkada, Yukinori1 aMoore, Kristjan, H S1 aMason, Dan1 aPirastu, Nicola1 aGandin, Ilaria1 aMattsson, Hannele1 aBarnes, Catriona, L K1 aLin, Kuang1 aZhao, Jing Hua1 aDeelen, Patrick1 aRohde, Rebecca1 aSchurmann, Claudia1 aGuo, Xiuqing1 aGiulianini, Franco1 aZhang, Weihua1 aMedina-Gómez, Carolina1 aKarlsson, Robert1 aBao, Yanchun1 aBartz, Traci, M1 aBaumbach, Clemens1 aBiino, Ginevra1 aBixley, Matthew, J1 aBrumat, Marco1 aChai, Jin-Fang1 aCorre, Tanguy1 aCousminer, Diana, L1 aDekker, Annelot, M1 aEccles, David, A1 avan Eijk, Kristel, R1 aFuchsberger, Christian1 aGao, He1 aGermain, Marine1 aGordon, Scott, D1 ade Haan, Hugoline, G1 aHarris, Sarah, E1 aHofer, Edith1 aHuerta-Chagoya, Alicia1 aIgartua, Catherine1 aJansen, Iris, E1 aJia, Yucheng1 aKacprowski, Tim1 aKarlsson, Torgny1 aKleber, Marcus, E1 aLi, Shengchao, Alfred1 aLi-Gao, Ruifang1 aMahajan, Anubha1 aMatsuda, Koichi1 aMeidtner, Karina1 aMeng, Weihua1 aMontasser, May, E1 avan der Most, Peter, J1 aMunz, Matthias1 aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 aConcas, Maria, Pina1 aCorley, Janie1 aCugliari, Giovanni1 avan Dam, Rob, M1 aDamulina, Anna1 aDaneshpour, Maryam, S1 aDay, Felix, R1 aDelgado, Graciela, E1 aDhana, Klodian1 aDoney, Alexander, S F1 aDörr, Marcus1 aDoumatey, Ayo, P1 aDzimiri, Nduna1 aEbenesersdóttir, Sunna1 aElliott, Joshua1 aElliott, Paul1 aEwert, Ralf1 aFelix, Janine, F1 aFischer, Krista1 aFreedman, Barry, I1 aGirotto, Giorgia1 aGoel, Anuj1 aGögele, Martin1 aGoodarzi, Mark, O1 aGraff, Mariaelisa1 aGranot-Hershkovitz, Einat1 aGrodstein, Francine1 aGuarrera, Simonetta1 aGudbjartsson, Daniel, F1 aGuity, Kamran1 aGunnarsson, Bjarni1 aGuo, Yu1 aHagenaars, Saskia, P1 aHaiman, Christopher, A1 aHalevy, Avner1 aHarris, Tamara, B1 aHedayati, Mehdi1 avan Heel, David, A1 aHirata, Makoto1 aHöfer, Imo1 aHsiung, Chao, Agnes1 aHuang, Jinyan1 aHung, Yi-Jen1 aIkram, Arfan, M1 aJagadeesan, Anuradha1 aJousilahti, Pekka1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerrison, Nicola, D1 aKessler, Thorsten1 aKhaw, Kay-Tee1 aKhor, Chiea, Chuen1 ade Kleijn, Dominique, P V1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKraft, Peter1 aKrämer, Bernhard, K1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLawlor, Deborah, A1 aLee, I-Te1 aLee, Wen-Jane1 aLerch, Markus, M1 aLi, Liming1 aLiu, Jianjun1 aLoh, Marie1 aLondon, Stephanie, J1 aLoomis, Stephanie1 aLu, Yingchang1 aLuan, Jian'an1 aMägi, Reedik1 aManichaikul, Ani, W1 aManunta, Paolo1 aMásson, Gísli1 aMatoba, Nana1 aMei, Xue, W1 aMeisinger, Christa1 aMeitinger, Thomas1 aMezzavilla, Massimo1 aMilani, Lili1 aMillwood, Iona, Y1 aMomozawa, Yukihide1 aMoore, Amy1 aMorange, Pierre-Emmanuel1 aMoreno-Macias, Hortensia1 aMori, Trevor, A1 aMorrison, Alanna, C1 aMuka, Taulant1 aMurakami, Yoshinori1 aMurray, Alison, D1 ade Mutsert, Renée1 aMychaleckyj, Josyf, C1 aNalls, Mike, A1 aNauck, Matthias1 aNeville, Matt, J1 aNolte, Ilja, M1 aOng, Ken, K1 aOrozco, Lorena1 aPadmanabhan, Sandosh1 aPálsson, Gunnar1 aPankow, James, S1 aPattaro, Cristian1 aPattie, Alison1 aPolasek, Ozren1 aPoulter, Neil1 aPramstaller, Peter, P1 aQuintana-Murci, Lluis1 aRäikkönen, Katri1 aRalhan, Sarju1 aRao, Dabeeru, C1 avan Rheenen, Wouter1 aRich, Stephen, S1 aRidker, Paul, M1 aRietveld, Cornelius, A1 aRobino, Antonietta1 avan Rooij, Frank, J A1 aRuggiero, Daniela1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSabater-Lleal, Maria1 aSala, Cinzia, Felicita1 aSalomaa, Veikko1 aSandow, Kevin1 aSchmidt, Helena1 aScott, Laura, J1 aScott, William, R1 aSedaghati-Khayat, Bahareh1 aSennblad, Bengt1 avan Setten, Jessica1 aSever, Peter, J1 aSheu, Wayne, H-H1 aShi, Yuan1 aShrestha, Smeeta1 aShukla, Sharvari, Rahul1 aSigurdsson, Jon, K1 aSikka, Timo, Tonis1 aSingh, Jai, Rup1 aSmith, Blair, H1 aStančáková, Alena1 aStanton, Alice1 aStarr, John, M1 aStefansdottir, Lilja1 aStraker, Leon1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSwertz, Morris, A1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTerzikhan, Natalie1 aTham, Yih-Chung1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTillander, Annika1 aTracy, Russell, P1 aTusié-Luna, Teresa1 aTzoulaki, Ioanna1 aVaccargiu, Simona1 aVangipurapu, Jagadish1 aVeldink, Jan, H1 aVitart, Veronique1 aVölker, Uwe1 aVuoksimaa, Eero1 aWakil, Salma, M1 aWaldenberger, Melanie1 aWander, Gurpreet, S1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWild, Sarah1 aYajnik, Chittaranjan, S1 aYuan, Jian-Min1 aZeng, Lingyao1 aZhang, Liang1 aZhou, Jie1 aAmin, Najaf1 aAsselbergs, Folkert, W1 aBakker, Stephan, J L1 aBecker, Diane, M1 aLehne, Benjamin1 aBennett, David, A1 avan den Berg, Leonard, H1 aBerndt, Sonja, I1 aBharadwaj, Dwaipayan1 aBielak, Lawrence, F1 aBochud, Murielle1 aBoehnke, Mike1 aBouchard, Claude1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarmi, Shai1 aCaulfield, Mark, J1 aCesarini, David1 aChambers, John, C1 aChandak, Giriraj, Ratan1 aCheng, Ching-Yu1 aCiullo, Marina1 aCornelis, Marilyn1 aCusi, Daniele1 aSmith, George Davey1 aDeary, Ian, J1 aDorajoo, Rajkumar1 aDuijn, Cornelia, M1 aEllinghaus, David1 aErdmann, Jeanette1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aEvans, Michele, K1 aFaul, Jessica, D1 aFeenstra, Bjarke1 aFeitosa, Mary1 aFoisy, Sylvain1 aFranke, Andre1 aFriedlander, Yechiel1 aGasparini, Paolo1 aGieger, Christian1 aGonzalez, Clicerio1 aGoyette, Philippe1 aGrant, Struan, F A1 aGriffiths, Lyn, R1 aGroop, Leif1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHakonarson, Hakon1 aHamsten, Anders1 aHarst, Pim1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHochner, Hagit1 aHuikuri, Heikki1 aHunt, Steven, C1 aJaddoe, Vincent, W V1 aDe Jager, Philip, L1 aJohannesson, Magnus1 aJohansson, Asa1 aJonas, Jost, B1 aJukema, Wouter1 aJunttila, Juhani1 aKaprio, Jaakko1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKumari, Meena1 aLaakso, Markku1 avan der Laan, Sander, W1 aLahti, Jari1 aLaudes, Matthias1 aLea, Rodney, A1 aLieb, Wolfgang1 aLumley, Thomas1 aMartin, Nicholas, G1 aMärz, Winfried1 aMatullo, Giuseppe1 aMcCarthy, Mark, I1 aMedland, Sarah, E1 aMerriman, Tony, R1 aMetspalu, Andres1 aMeyer, Brian, F1 aMohlke, Karen, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis1 aMunroe, Patricia, B1 aNorth, Kari, E1 aNyholt, Dale, R1 aO'Connell, Jeffery, R1 aOber, Carole1 aOldehinkel, Albertine, J1 aPalmas, Walter1 aPalmer, Colin1 aPasterkamp, Gerard, G1 aPatin, Etienne1 aPennell, Craig, E1 aPerusse, Louis1 aPeyser, Patricia, A1 aPirastu, Mario1 aPolderman, Tinca, J C1 aPorteous, David, J1 aPosthuma, Danielle1 aPsaty, Bruce, M1 aRioux, John, D1 aRivadeneira, Fernando1 aRotimi, Charles1 aRotter, Jerome, I1 aRudan, Igor1 aRuijter, Hester, M den1 aSanghera, Dharambir, K1 aSattar, Naveed1 aSchmidt, Reinhold1 aSchulze, Matthias, B1 aSchunkert, Heribert1 aScott, Robert, A1 aShuldiner, Alan, R1 aSim, Xueling1 aSmall, Neil1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aTai, E-Shyong1 aTeumer, Alexander1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTrégouët, David-Alexandre1 aTuomi, Tiinamaija1 aVollenweider, Peter1 aWang, Carol, A1 aWeir, David, R1 aWhitfield, John, B1 aWijmenga, Cisca1 aWong, Tien-Yin1 aWright, John1 aYang, Jingyun1 aYu, Lei1 aZemel, Babette, S1 aZonderman, Alan, B1 aPerola, Markus1 aMagnusson, Patrik, K E1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aChasman, Daniel, I1 aLoos, Ruth, J F1 aFranceschini, Nora1 aFranke, Lude1 aHaley, Chris, S1 aHayward, Caroline1 aWalters, Robin, G1 aPerry, John, R B1 aEsko, Tõnu1 aHelgason, Agnar1 aStefansson, Kari1 aJoshi, Peter, K1 aKubo, Michiaki1 aWilson, James, F uhttps://chs-nhlbi.org/node/819804831nas a2201009 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a1941-722500aGenome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.0 aGenomeWide Association Study of Apparent TreatmentResistant Hype c2019 Nov 15 a1146-11530 v323 aBACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
10aAged10aAntihypertensive Agents10aBlack or African American10aBlood Pressure10aCase-Control Studies10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methyltransferase 3A10aDNA-Binding Proteins10aDrug Resistance10aDystrophin-Associated Proteins10aEurope10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMyosin Heavy Chains10aMyosin Type V10aNeuropeptides10aPharmacogenetics10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aRisk Assessment10aRisk Factors10aTranscription Factors10aUnited States10aWhite People1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aFloyd, James, S1 aPsaty, Bruce, M1 aBis, Joshua, C1 aWiggins, Kerri, L1 aWhitsel, Eric, A1 aStürmer, Til1 aStewart, James1 aRaffield, Laura1 aSun, Fangui1 aLiu, Ching-Ti1 aXu, Hanfei1 aCupples, Adrienne, L1 aTanner, Rikki, M1 aRossing, Peter1 aSmith, Albert1 aZilhão, Nuno, R1 aLauner, Lenore, J1 aNoordam, Raymond1 aRotter, Jerome, I1 aYao, Jie1 aLi, Xiaohui1 aGuo, Xiuqing1 aLimdi, Nita1 aSundaresan, Aishwarya1 aLange, Leslie1 aCorrea, Adolfo1 aStott, David, J1 aFord, Ian1 aJukema, Wouter1 aGudnason, Vilmundur1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aPalmas, Walter1 aWarren, Helen, R1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aO'donnell, Christopher1 aHung, Adriana, M1 aEdwards, Todd, L1 aAhluwalia, Tarunveer, S1 aArnett, Donna, K1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/937204711nas a2201357 4500008004100000022001400041245009500055210006900150260001300219300001000232490000700242520077200249100001601021700002501037700002101062700001701083700002001100700002101120700002401141700002201165700001601187700002001203700003001223700002701253700002201280700002301302700002301325700002101348700001801369700001501387700001301402700002501415700002401440700002001464700002101484700002001505700001901525700003301544700002301577700002101600700002001621700001801641700001901659700002101678700002701699700001501726700002701741700001901768700002001787700001801807700002301825700002101848700001901869700002101888700002301909700001901932700002401951700002101975700001601996700002102012700002302033700001602056700002202072700002002094700002102114700001902135700002402154700001702178700002102195700002402216700002502240700001702265700003002282700001602312700002302328700002002351700001902371700003202390700002302422700002102445700002402466700002202490700002002512700002702532700002302559700002502582700001602607700002102623700001502644700002402659700002002683700002202703700002302725700002202748700002102770700002002791700002402811700002402835700002902859700002302888700001802911700002102929700001802950700002302968700002002991700002803011700002103039700003003060700002103090700002103111710004303132710004803175710006603223710002803289856003603317 2019 eng d a1546-171800aTrans-ethnic association study of blood pressure determinants in over 750,000 individuals.0 aTransethnic association study of blood pressure determinants in c2019 Jan a51-620 v513 aIn this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
1 aGiri, Ayush1 aHellwege, Jacklyn, N1 aKeaton, Jacob, M1 aPark, Jihwan1 aQiu, Chengxiang1 aWarren, Helen, R1 aTorstenson, Eric, S1 aKovesdy, Csaba, P1 aSun, Yan, V1 aWilson, Otis, D1 aRobinson-Cohen, Cassianne1 aRoumie, Christianne, L1 aChung, Cecilia, P1 aBirdwell, Kelly, A1 aDamrauer, Scott, M1 aDuVall, Scott, L1 aKlarin, Derek1 aCho, Kelly1 aWang, Yu1 aEvangelou, Evangelos1 aCabrera, Claudia, P1 aWain, Louise, V1 aShrestha, Rojesh1 aMautz, Brian, S1 aAkwo, Elvis, A1 aSargurupremraj, Muralidharan1 aDebette, Stephanie1 aBoehnke, Michael1 aScott, Laura, J1 aLuan, Jian'an1 aZhao, Jing-Hua1 aWillems, Sara, M1 aThériault, Sébastien1 aShah, Nabi1 aOldmeadow, Christopher1 aAlmgren, Peter1 aLi-Gao, Ruifang1 aVerweij, Niek1 aBoutin, Thibaud, S1 aMangino, Massimo1 aNtalla, Ioanna1 aFeofanova, Elena1 aSurendran, Praveen1 aCook, James, P1 aKarthikeyan, Savita1 aLahrouchi, Najim1 aLiu, Chunyu1 aSepúlveda, Nuno1 aRichardson, Tom, G1 aKraja, Aldi1 aAmouyel, Philippe1 aFarrall, Martin1 aPoulter, Neil, R1 aLaakso, Markku1 aZeggini, Eleftheria1 aSever, Peter1 aScott, Robert, A1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aConen, David1 aPalmer, Colin, Neil Alexa1 aAttia, John1 aChasman, Daniel, I1 aRidker, Paul, M1 aMelander, Olle1 aMook-Kanamori, Dennis, Owen1 avan der Harst, Pim1 aCucca, Francesco1 aSchlessinger, David1 aHayward, Caroline1 aSpector, Tim, D1 aJarvelin, Marjo-Riitta1 aHennig, Branwen, J1 aTimpson, Nicholas, J1 aWei, Wei-Qi1 aSmith, Joshua, C1 aXu, Yaomin1 aMatheny, Michael, E1 aSiew, Edward, E1 aLindgren, Cecilia1 aHerzig, Karl-Heinz1 aDedoussis, George1 aDenny, Joshua, C1 aPsaty, Bruce, M1 aHowson, Joanna, M M1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aCaulfield, Mark, J1 aElliott, Paul1 aGaziano, Michael1 aConcato, John1 aWilson, Peter, W F1 aTsao, Philip, S1 aEdwards, Digna, R Velez1 aSusztak, Katalin1 aO'Donnell, Christopher, J1 aHung, Adriana, M1 aEdwards, Todd, L1 aUnderstanding Society Scientific Group1 aInternational Consortium for Blood Pressure1 aBlood Pressure-International Consortium of Exome Chip Studies1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/791409368nas a2202785 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2020 eng d a1476-557800aGene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.0 aGeneeducational attainment interactions in a multiancestry genom c2020 May 053 aEducational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
1 aFuentes, Lisa, de Las1 aSung, Yun, Ju1 aNoordam, Raymond1 aWinkler, Thomas1 aFeitosa, Mary, F1 aSchwander, Karen1 aBentley, Amy, R1 aBrown, Michael, R1 aGuo, Xiuqing1 aManning, Alisa1 aChasman, Daniel, I1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aCheng, Ching-Yu1 aDorajoo, Rajkumar1 aHartwig, Fernando, P1 aHorimoto, A, R V R1 aLi, Changwei1 aLi-Gao, Ruifang1 aLiu, Yongmei1 aMarten, Jonathan1 aMusani, Solomon, K1 aNtalla, Ioanna1 aRankinen, Tuomo1 aRichard, Melissa1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVojinovic, Dina1 aWarren, Helen, R1 aXuan, Deng1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin-Fang1 aChen, Xu1 aChristensen, Kaare1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGirotto, Giorgia1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLi, Xiaoyin1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRueedi, Rico1 aShu, Xiao-Ou1 aSnieder, Harold1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aYanek, Lisa, R1 aAmin, Najaf1 aArking, Dan, E1 aArnett, Donna, K1 aBergmann, Sven1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBrumat, Marco1 aBurke, Gregory1 aCabrera, Claudia, P1 aCanouil, Mickaël1 aChee, Miao, Li1 aChen, Yii-Der Ida1 aCocca, Massimiliano1 aConnell, John1 ade Silva, Janaka1 ade Vries, Paul, S1 aEiriksdottir, Gudny1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFox, Ervin, F1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven1 aIkram, Arfan, M1 aIrvin, Marguerite, R1 aKähönen, Mika1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKraja, Aldi, T1 aKrieger, J, E1 aLangefeld, Carl, D1 aLi, Yize1 aLiang, Jingjing1 aLiewald, David, C M1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLohman, Kurt, K1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMook-Kanamori, Dennis, O1 aNalls, Mike, A1 aNelson, Christopher, P1 aNorris, Jill, M1 aO'Connell, Jeff1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPedersen, Nancy, L1 aPerls, Thomas1 aPeters, Annette1 aPetersmann, Astrid1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aRaffel, Leslie, J1 aRice, Treva, K1 aRotter, Jerome, I1 aRudan, Igor1 aRueda-Ochoa, Oscar-Leonel1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSchreiner, Pamela, J1 aShikany, James, M1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTeumer, Alexander1 aTham, Yih, Chung1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Ende, Yldau1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWeir, David, R1 aWen, Wanqing1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBowden, Donald, W1 aDeary, Ian, J1 aDörr, Marcus1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aMarques-Vidal, Pedro1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aCooper, Richard, S1 aCorrea, Adolfo1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aPalmas, Walter, R1 aPereira, A, C1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotimi, Charles, N1 aTai, Shyong, E1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aRice, Kenneth1 aGauderman, James1 aMorrison, Alanna, C1 aNorth, Kari, E1 aKardia, Sharon, L R1 aCaulfield, Mark, J1 aElliott, Paul1 aMunroe, Patricia, B1 aFranks, Paul, W1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/838107958nas a2202377 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2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836802876nas a2200337 4500008004100000022001400041245014800055210006900203260000900272300001100281490000700292520184000299100002002139700001802159700002102177700002102198700002202219700002302241700001602264700002202280700002302302700002202325700002402347700002202371700002002393700002302413700001902436700002502455700002202480856003602502 2021 eng d a1663-981200aThe Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.0 aPharmacogenetics of Statin Therapy on Clinical Events No Evidenc c2021 a6798570 v123 aThe pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.
1 aTrompet, Stella1 aPostmus, Iris1 aWarren, Helen, R1 aNoordam, Raymond1 aSmit, Roelof, A J1 aTheusch, Elizabeth1 aLi, Xiaohui1 aArsenault, Benoit1 aChasman, Daniel, I1 aHitman, Graham, A1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aKrauss, Ron, M1 aCupples, Adrienne, L1 aJukema, Wouter, J uhttps://chs-nhlbi.org/node/898005976nas a2201393 4500008004100000022001400041245013400055210006900189260001600258300003400274520189200308100002102200700001402221700001702235700002202252700003002274700002502304700002502329700001502354700002302369700002302392700001702415700002002432700002202452700001302474700001902487700002402506700001902530700001802549700002302567700001902590700002602609700001602635700002302651700002402674700002102698700002902719700002202748700001602770700001902786700001802805700002102823700001802844700002602862700002202888700002102910700001802931700001602949700002002965700001902985700001803004700002403022700002503046700002203071700002103093700002203114700001703136700001703153700002003170700002103190700003303211700002403244700001703268700002203285700003403307700002503341700002203366700002103388700002103409700001903430700002203449700002003471700001903491700001403510700002503524700002103549700002503570700001703595700001403612700002303626700001803649700001703667700002203684700002103706700002203727700002403749700002103773700001903794700002203813700002103835700001903856700002603875700002103901700002003922700001903942700001903961700002503980700002004005700002304025700002404048700002204072700002304094700001404117700002004131700002004151700002004171700001904191700002104210700002204231700002404253700002104277700002504298700001804323700001704341700002104358700002404379710014304403856003604546 2022 eng d a1524-456300aInsights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.0 aInsights From a LargeScale WholeGenome Sequencing Study of Systo c2022 Jun 02 a101161HYPERTENSIONAHA122193243 aBACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.
METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.
RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).
DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
1 aKelly, Tanika, N1 aSun, Xiao1 aHe, Karen, Y1 aBrown, Michael, R1 aTaliun, Sarah, A Gagliano1 aHellwege, Jacklyn, N1 aIrvin, Marguerite, R1 aMi, Xuenan1 aBrody, Jennifer, A1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 ade Vries, Paul, S1 aGao, Yan1 aMoscati, Arden1 aNadkarni, Girish, N1 aYanek, Lisa, R1 aElfassy, Tali1 aSmith, Jennifer, A1 aChung, Ren-Hua1 aBeitelshees, Amber, L1 aPatki, Amit1 aAslibekyan, Stella1 aBlobner, Brandon, M1 aPeralta, Juan, M1 aAssimes, Themistocles, L1 aPalmas, Walter, R1 aLiu, Chunyu1 aBress, Adam, P1 aHuang, Zhijie1 aBecker, Lewis, C1 aHwa, Chii-Min1 aO'Connell, Jeffrey, R1 aCarlson, Jenna, C1 aWarren, Helen, R1 aDas, Sayantan1 aGiri, Ayush1 aMartin, Lisa, W1 aJohnson, Craig1 aFox, Ervin, R1 aBottinger, Erwin, P1 aRazavi, Alexander, C1 aVaidya, Dhananjay1 aChuang, Lee-Ming1 aChang, Yen-Pei, C1 aNaseri, Take1 aJain, Deepti1 aKang, Hyun, Min1 aHung, Adriana, M1 aSrinivasasainagendra, Vinodh1 aSnively, Beverly, M1 aGu, Dongfeng1 aMontasser, May, E1 aReupena, Muagututi'a, Sefuiva1 aHeavner, Benjamin, D1 aLeFaive, Jonathon1 aHixson, James, E1 aRice, Kenneth, M1 aWang, Fei, Fei1 aNielsen, Jonas, B1 aHuang, Jianfeng1 aKhan, Alyna, T1 aZhou, Wei1 aNierenberg, Jovia, L1 aLaurie, Cathy, C1 aArmstrong, Nicole, D1 aShi, Mengyao1 aPan, Yang1 aStilp, Adrienne, M1 aEmery, Leslie1 aWong, Quenna1 aHawley, Nicola, L1 aMinster, Ryan, L1 aCurran, Joanne, E1 aMunroe, Patricia, B1 aWeeks, Daniel, E1 aNorth, Kari, E1 aTracy, Russell, P1 aKenny, Eimear, E1 aShimbo, Daichi1 aChakravarti, Aravinda1 aRich, Stephen, S1 aReiner, Alex, P1 aBlangero, John1 aRedline, Susan1 aMitchell, Braxton, D1 aRao, Dabeeru, C1 aChen, Yii-Der, Ida1 aKardia, Sharon, L R1 aKaplan, Robert, C1 aMathias, Rasika, A1 aHe, Jiang1 aPsaty, Bruce, M1 aFornage, Myriam1 aLoos, Ruth, J F1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aKooperberg, Charles1 aEdwards, Todd, L1 aAbecasis, Goncalo, R1 aZhu, Xiaofeng1 aLevy, Daniel1 aArnett, Donna, K1 aMorrison, Alanna, C1 aNHLBI Trans-Omics for Precision Medicine TOPMed) Consortium, The Samoan Obesity, Lifestyle, and Genetic Adaptations Study (OLaGA) Group† uhttps://chs-nhlbi.org/node/909905138nas a2201357 4500008004100000022001400041245012700055210006900182260001600251300000900267490000700276520124600283653002501529653002701554653001501581653002801596653002401624653003401648653001101682653001701693100002201710700002201732700002601754700001901780700001301799700001801812700002201830700001901852700002001871700002901891700002701920700002401947700001801971700001601989700002202005700001302027700002102040700002002061700001902081700002602100700002402126700001902150700002702169700002002196700002602216700002202242700001902264700002302283700002102306700001902327700001902346700002102365700002702386700002402413700002702437700001502464700002302479700001702502700001902519700002302538700002402561700001702585700003202602700002102634700002502655700002402680700001702704700002302721700002602744700002502770700001802795700002102813700001402834700002402848700002402872700001802896700002902914700001902943700002502962700001802987700002103005700002103026700002203047700001903069700002203088700001703110700002103127700001803148700002203166700001903188700002903207700002803236700002503264700002003289700002203309700002903331700002203360700002303382700001503405700002303420700001803443700002103461700001903482700002203501700001803523700002403541700001803565700002103583700002403604700002203628700002003650700002203670700002803692700002403720856003603744 2023 eng d a2041-172300aGenetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.0 aGenetic architecture of spatial electrical biomarkers for cardia c2023 Mar 14 a14110 v143 aThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
10aArrhythmias, Cardiac10aAtrioventricular Block10aBiomarkers10aCardiovascular Diseases10aElectrocardiography10aGenome-Wide Association Study10aHumans10aRisk Factors1 aYoung, William, J1 aHaessler, Jeffrey1 aBenjamins, Jan-Walter1 aRepetto, Linda1 aYao, Jie1 aIsaacs, Aaron1 aHarper, Andrew, R1 aRamirez, Julia1 aGarnier, Sophie1 aVan Duijvenboden, Stefan1 aBaldassari, Antoine, R1 aConcas, Maria, Pina1 aDuong, ThuyVy1 aFoco, Luisa1 aIsaksen, Jonas, L1 aMei, Hao1 aNoordam, Raymond1 aNursyifa, Casia1 aRichmond, Anne1 aSantolalla, Meddly, L1 aSitlani, Colleen, M1 aSoroush, Negin1 aThériault, Sébastien1 aTrompet, Stella1 aAeschbacher, Stefanie1 aAhmadizar, Fariba1 aAlonso, Alvaro1 aBrody, Jennifer, A1 aCampbell, Archie1 aCorrea, Adolfo1 aDarbar, Dawood1 aDe Luca, Antonio1 aDeleuze, Jean-Francois1 aEllervik, Christina1 aFuchsberger, Christian1 aGoel, Anuj1 aGrace, Christopher1 aGuo, Xiuqing1 aHansen, Torben1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aKors, Jan, A1 aLima-Costa, Maria, Fernanda1 aLinneberg, Allan1 aMacfarlane, Peter, W1 aMorrison, Alanna, C1 aNavarro, Pau1 aPorteous, David, J1 aPramstaller, Peter, P1 aReiner, Alexander, P1 aRisch, Lorenz1 aSchotten, Ulrich1 aShen, Xia1 aSinagra, Gianfranco1 aSoliman, Elsayed, Z1 aStoll, Monika1 aTarazona-Santos, Eduardo1 aTinker, Andrew1 aTrajanoska, Katerina1 aVillard, Eric1 aWarren, Helen, R1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aArking, Dan, E1 aAvery, Christy, L1 aConen, David1 aGirotto, Giorgia1 aGrarup, Niels1 aHayward, Caroline1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aOlesen, Morten, Salling1 aPadmanabhan, Sandosh1 aPsaty, Bruce, M1 aPattaro, Cristian1 aRibeiro, Antonio, Luiz P1 aRotter, Jerome, I1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aWilson, James, G1 aOrini, Michele1 aCharron, Philippe1 aWatkins, Hugh1 aKooperberg, Charles1 aLin, Henry, J1 aWilson, James, F1 aKanters, Jørgen, K1 aSotoodehnia, Nona1 aMifsud, Borbala1 aLambiase, Pier, D1 aTereshchenko, Larisa, G1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/932203534nas a2200649 4500008004100000245010900041210006900150260001600219520168900235100002201924700001601946700002001962700002201982700001402004700002202018700001602040700002202056700002402078700002002102700002202122700001702144700002402161700001802185700002102203700002302224700002402247700001902271700002102290700002002311700001902331700002202350700002002372700001902392700002002411700001702431700001902448700001702467700002502484700002402509700001902533700002302552700001902575700002302594700002002617700002102637700001802658700002002676700002202696700002402718700002102742700002002763700001802783700001402801700001702815700001602832856003602848 2023 eng d00aGenome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.0 aGenomeWide Interaction Analysis with DASH Diet Score Identified c2023 Nov 113 aOBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).
METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.
RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.
CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
1 aGuirette, Melanie1 aLan, Jessie1 aMcKeown, Nicola1 aBrown, Michael, R1 aChen, Han1 ade Vries, Paul, S1 aKim, Hyunju1 aRebholz, Casey, M1 aMorrison, Alanna, C1 aBartz, Traci, M1 aFretts, Amanda, M1 aGuo, Xiuqing1 aLemaitre, Rozenn, N1 aLiu, Ching-Ti1 aNoordam, Raymond1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aWang, Carol, A1 aBeilin, Lawrence1 aMori, Trevor, A1 aOddy, Wendy, H1 aPennell, Craig, E1 aChai, Jin, Fang1 aWhitton, Clare1 avan Dam, Rob, M1 aLiu, Jianjun1 aTai, Shyong, E1 aSim, Xueling1 aNeuhouser, Marian, L1 aKooperberg, Charles1 aTinker, Lesley1 aFranceschini, Nora1 aHuan, Tianxiao1 aWinkler, Thomas, W1 aBentley, Amy, R1 aGauderman, James1 aHeerkens, Luc1 aTanaka, Toshiko1 avan Rooij, Jeroen1 aMunroe, Patricia, B1 aWarren, Helen, R1 aVoortman, Trudy1 aChen, Honglei1 aRao, D, C1 aLevy, Daniel1 aMa, Jiantao uhttps://chs-nhlbi.org/node/9583